TGR5 receptor is a G-protein-coupled receptor that has been identified as a cell-surface receptor that is responsive to bile acids. The primary structure of TGR5 and its responsiveness to bile acids has been found to be highly conserved in TGR5 among human, bovine, rabbit, rat, and mouse, and thus suggests that TGR5 has important physiological functions. TGR5 has been found to be widely distributed in not only lymphoid tissues but also in other tissues. High levels of TGR5 mRNA have been detected in placenta, spleen, and monocytes/macrophages. Bile acids have been shown to induce internalization of the TGR5 fusion protein from the cell membrane to the cytoplasm. Kawamata et al. 2003, J. Bio. Chem., 278, 9435. TGR5 has been found to be identical to hGPCR19 reported by Takeda et al. 2002, FEBS Lett. 520, 97-101.
Bile acids are cholesterol metabolites that are formed in the liver and secreted into the duodenum of the intestine. Bile acids are compounds that play essential roles in the absorption of dietary lipids and regulation of bile acid synthesis. For example, Farnesoid X receptor (FXR) and pregnane X receptor (PXR) have recently been identified as specific nuclear receptors for bile acids. Through activation of FXR, bile acids repress the expression of the rate-limiting enzyme in bile acid synthesis, cholesterol 7a-hydroxylase (Cyp7a). The activation of PXR by bile acids results in both the repression of Cyp7a and the transcriptional induction of the bile acid-metabolizing enzyme, cytochrome P450 3a. At high concentrations, bile acids are also known to exhibit immunosuppressive effects on cell-mediated immunity and macrophage functions. Bile acids including deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) have been demonstrated to have inhibitory activities on the lipopolysaccharide (LPS)-induced promotion of cytokines in macrophages, including interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNFα).
Bile acid compounds that modulate TGR5 have been used for the treatment of various diseases, including central nervous diseases as well as inflammatory diseases (WO 01/77325 and WO 02/84286). Specifically, bile acid compounds alkylated in position 6 of cholanic acid have been disclosed in WO 02/072598, WO 2004/0007521, and EP 1568706 as FXR agonists. The bile acid compound, 23-methyl-ursodeoxycholic (3-alpha,7-beta-dihydroxy-5-beta-cholan-24-oic acid) has also been disclosed (Hepatology, 1988, 8(6), 1571-1576) for the treatment of cholestatic liver diseases.

Modulators of TGR5 provide methods of regulating bile acid and cholesterol homeostasis, fatty acid absorption, and protein and carbohydrate digestion. There is a need for the development of TGR5 modulators for the treatment and/or prevention of various diseases. The present invention has identified compounds that modulate TGR5 as well as methods of using these compounds to treat disorders such as central nervous system diseases, inflammatory diseases, and metabolic diseases such as obesity and insulin sensitivity. Methods of using the compounds of the invention also include to prevent disorders such as central nervous diseases, inflammatory diseases, and metabolic diseases e.g., metabolic syndrome, Type 2 diabetes, obesity, etc.